3-heterocyclic thiomethyl-cephalosporins

ABSTRACT

Cephalosporin compounds substituted at the 7-position with free or substituted Alpha -amino or hydroxy phenylacetamido and at the 3-position with a heterocyclic thiomethyl group are prepared by displacement of a 3-acetoxy-methyl compound with a mercaptoheterocycle or by 7-acylation. The products are antibacterial agents.

United States Patent [1 1 Dunn et al.

1. [45] Dec. 17, 1974 S-HETEROCYCLIC THIOMETHYL-CEPHALOSPORINS [75]Inventors: George L. Dunn, Wayne; John R. E.

- Hoover, Glenside, both of Pa.

[73] Assignee: Smith Kline & French Laboratories,

Philadelphia, Pa.

[22] Filed: Sept. 15, 1972 [21] Appl. No.1 289,499

Related US. Application Data [63] Continuation-impart of Ser. Nos.116,599, Feb. 18, 1971, and Ser. No. 262,903, June 14, 1972, which is acontinuation-in-part of Ser. No. 116,598, Feb. 18, 1971, abandoned,which is a continuation-in-part of Ser. No. 99,296, Dec. 17, 1970,abandoned, said Ser. No. 116,599, is a continuation-in-part of Ser. No.99,296.

[30] Foreign Application Priority Data Nov. 8, 1971 South Africa 71/7457[52] US. Cl. 260/243 C, 424/246 [51] Int. Cl C07d 99/24 PrimaryExaminerNicholas S. Rizzo Attorney, Agent, or FirmA1an D. Lourie;William H.

Edgerton [5 7] ABSTRACT Cephalosporincompounds substituted at the 7-position with free or substituted a-amino or hydroxy phenylacetamido andat the 3-position with a heterocyclic thiomethyl group are prepared bydisplacement of a 3-acetoxy-methy1 compound with a mercaptoheterocycleor by 7-acy1ation. The products are antibacterial agents.

12 Claims, No Drawings -HET OC CLIQ THlOMETHYL-CEPHALOSPORINS Thisapplication is a continuation-in-part of copending application Ser. No.116,599, filed Feb. 18, 1971, which was a continuation-in-part ofapplication Ser. No. 99,296, filed Dec. 17, 1970, now abandoned, and itis also a continuation-in-part of copending application Ser. No.262,903, filed June 14, 1972, which is a continuation-in-part ofapplication Ser. No. 116,598, filed Feb. 18, 1971, now abandoned, whichapplication was a continuation-in-part of application Ser. No. 99,296,filed Dec. 17, 1970, now abandoned.

This invention relates to chemical compounds known as cephalosphorins,which compounds possess antibacterial activity. 7

The compounds of this invention are represented by the followingstructural formula:

in which:

X and X are each hydrogen, lower alkyl of l-4 carbon atoms, lower alkoxyof l-4 carbon atoms, hydroxy, hydroxymethyl, halo, nitro, amino,mercapto, lower alkylthio of 1-4 carbon atoms, aminomethyl ortrifluoromethyl;

Y is Nl-l or OH;

R is triazolyl, or imidazolyl, each of which is unsubstituted orsubstituted with l or 2 R ring substituents such as lower alkyl of up to4 carbons, cycloalkyl of up to 6 carbons, alkenyl of up to 6 carbons,lower alkoxy of up to 4 carbons, lower alkoxyalkyl of 2 to 8 carbons, CFNl-l alkylamino, dialkylamino, phenyl, methylthio, or halogen, and

M is hydrogen or an alkali metal.

Examples of R groups are:

2 2 N-N N--N--R N,-N

| I R2 u 1 R2 1 L 2 I R2 R N N l '1 l l I l R l" 2 N l L R N i 2 R2 Apreferred group of compounds within the scope of Formula 1 is that inwhich X is p-HO, X is H, R is triazolyl, and Y is NH These compoundshave highly advantageous properties as antibacterial agents.

The compounds of the present invention are prepared by reaction of acompound differing from one of Formula 1 in that the 3-substituent isacetoxymethyl rather than R -thiomethyl with a mercaptoheterocycle.

a-amino group on the phenylglycine starting material should be protectedwith a readily removable group such as t-butoxycarbonyl, carbobenzyloxyor trichloroethoxycarbonyl. The displacement at the 3- position is thenconducted, followed by removal of the protective group in theconventional manner.

The compounds of the invention may also be prepared by acylating the7-position of the appropriate 7-amino-3-heterocyclic thiomethylcephalosphorin nu cleus with a phenylglycine or mandelic acid. Prior toacylation, it is desirable to protect the amino group on the glycinemoiety with an easily removable protective group such ast-butoxycarbonyl, benzyloxycarbonyl, trichloroethoxycarbonyl, or similarprotective group commonly used in the synthesis of peptides. Similarly,the hydroxy group of the mandelic acid moiety can be protected byconversion to the dichloroacetoxy, tetrahydropyranyloxy,trimethylsilyoxy, formyloxy, or similar known protected derivative. Foracylation, the carboxyl group of the acylating agent can be activated byconversion to the acid chloride or to a mixed anhydridewith, forexample, a lower alkyl chloroformate. The carboxyl group can also beactivated by conversion to the 2,4-dinitrophenyl ester. If an ester ofthe cephalosporin nucleus, for example, the benzhydryl, t-butyl,trichloroethyl, or a benzyl ester, is used, the protected phenylglycineor mandelic acid can be coupled directly to the 7-amino group by using acarbodiimide such dicyclohexylcarbodiimide. Alternatively, the protectedphenylglycine or mandelic acid can be activated for condensation withthe appropriate cephalosporin' nucleus by reacting it first withcarbonyldiimidazole or its equivalent.

The starting materials for use in the first process, i.e.,3-displacement of a 7-acylated cephalosporanic acid, are described inthe literature or obtainable by known methods. The starting materialsfor use in the second process, i.e. 7-acylation of a 3-heterocyclicthiomethyl nucleus, are prepared by displacing the 3-acetoxy group of analkali metal salt of 7-aminocephalosporanic acid (7-ACA) with an alkalimetal salt of the heterocyclic thiol in, for example, hot aqueousacetone.

It is recognized that due to the asymetric a-carbon in the 7-acetamidogroup optical isomers will exist. The D isomer is the preferred isomer;however, the L isomer and the racemic mixture are also within the scopeof this invention.

The starting materials for preparing the products of this invention areknown, readily preparable by known methods, or described herein.

The products of this invention are antibacterial 5 agents active againstGram-negative and Gram-positive En terobacter aerogenes. A larger numberof compounds within the scope of Formula I have been prepared and allhave had antibacterial activity in an in vitro testing program.Compounds where X is p-Ol-l, X is H, R is triazolyl, and Y is NH areespecially advantageous in that they exhibit higher blood levels andlower PD s than related compounds.

The compounds are formulated into injectable or oral formulations in thesame manner as other cephalosporin antibiotics. They are administered byinjection or orally to prevent and treat bacterial infections in doseswhich will vary with the nature and severity of the infection and theage, weight, and condition of the subject.

Due to the presence of both an amine group and a carboxylic acid groupin certain of the cephalosporin compounds of this invention, it ispossible, by standard methods, to prepare both acid and base salts ofpharmaceutically acceptable nontoxic acids and bases as well as thezwitterionic forms of the compounds. Salts, when obtained, are readilyconverted to the zwitterions by known methods. It is to be understoodthat these salts are included within the scope of this invention.

The following examples are intended to illustrate the preparation of theproducts of the invention, but are not to be construed as limiting thescope thereof. Temperatures are in degrees Centigrade.

EXAMPLE 1 3-( 3 ,4-Dimethyl-l,2,4-triazol-S-ylthiomethyl)-7-(aaminophenylacetamido)-3mol.) -carboxylic acid was added 7-ACA (6.8 g., 0.025 mol.), water (50 ml.) and acetone(25 -triazole 4 To a solution of NaHCO (4.2 g., 0.05 mol. in water (50ml.) and acetone (25 ml.). The resulting solution was warmed to 45 andthen a solution of 3,4-dimethyl- 5-mercapto-1,2,4-traizole (5.0 g.,0.038 mol.) in acetone (50 ml.) and 55 NaHCO ml.) was added. Thereaction was refluxed until the reaction was completed as determined bythe disappearance of the acetoxy carbonyl band in the infraredabsorption spectrum. During this time the pH'was maintained at ca. 7.6.The solution was cooled to 10 and adjusted to pH 3.5 with 3N HCl. Theprecipitated product was collected, washed with acetone, and dried togive a 60 percent yield of 3-(3,4- dimethyl-l,2,4-triazol-5-ylthiomethyl )-7-amino-3- cephem-4-carboxylic acid.

To a cold solution (10) of a-t-butoxycarboxamidophenylacetic acid (2.26g., 0.013 mol.) and triethylamine (1.4 ml., 0.013 mol.) in drytetrahydrofuran (50 ml.) was added with stirring isobutyl chloroformate(1.5 ml., 0.013 mol.) over a 10 minute period. To this was addeddropwise at 10 a cold solution of the above 7-ACA derivativetriethylamine salt [prepared by adding triethylamine (1.5 ml., 0.013mole) to a suspension of 7-ACA compound (5.0 g., 0.013 mol.) in 40 ml.50 percent aq. tetrahydrofuran]. The reaction solution was stirred 1hour at 0 and 1.5 hours at room temperature. The tetrahydrofuran wasevaporated, water added to the mixture, and extracted with ethylacetate. The organic layer was discarded. The aqueous phase was cooled,layered with ethyl acetate, and acidified to pH 3 using 3N HCl. Thephases were separated and the aqueous phase was extracted with ethylacetate. Evaporation of the combined and dried organic layers gave asolid. Trituration with ether-petroleum ether ether followed byrecrystallization from methylene ch1orideether gave the puret-butoxycarbonyl derivative.

The above product (6.5 g.) was added to cold trifluoroacetic acid (65ml.) and stirred at 0. The solution was poured slowly into a largevolume of ether and the precipitated trifluoroacetate salt wascollected. Alternatively, the trifluoroacetate salt may be isolated byevaporating the excess trifluoroacetic acid and triturating the residuewith ether.

The trifluoroacetate salt (5.3 g.) was dissolved in water (25 ml.) and15 g. of a polystyrene-amine ionexchange resin, Amberlite 1R-45, wasadded. After stirring 1 hour at room temperature the resin was filteredoff and the aqueous solution was lyophilized to yield the titlecompound.

An alternative procedure to obtain the zwitterion involved dissolutionof the trifluoroacetate salt in water, addition of methyl isobutylketone (MlBK) and, while stirring, adjustment of the solution to pH 4using tri-nbutylamine. The solid product was collected, washed with MIBKand ethyl acetate, and dried. Calculated for C l-l N O S J5H OI C, H, N,Found: C, 48.03; H, 4.66; N, 16.75.

EXAMPLE 2 7-(a-Aminophenylacetamido)3-( 1,2,4-triazol-3ylthiomethyl)-3-cephem-4-carboxylic acid When 3-mercapto-1 ,2,4-triazolewas reacted according to the procedure of Example 1, the title compoundwas obtained; mp. (dec.). Calculated for C H N O S H O: C, 46.54; H,4.34; N, 18.09; Found: C, 46.69; H, 4.34; N, 17.77.

EXAMPLE 3 7-(a-Aminophenylacetamido)-3-(2-methy1-1,2,4-triazole-3-ylthiomethyl)-3-cephem-4-carboxylic acid3-Mercapto-2-methyl-l,2,4-triazole was reacted according to theprocedure of Example 1 to yield the title compound; m.p. 220 (dec.);Calculated for C, H N O S H O: C, 48.60; H, 4.51; N, 17.90; Found: C,48.82; H, 4.42; N, 17.78.

EXAMPLE 4 7-(a-Aminophenylacetamido)-3-(4-methy1-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid When3-mercapto-4-methyl-1,2,4-triazole was used in the procedure of Example1, the title compound was obtained. Calculated for C H N O S .2H O: C,45.96; H, 4.87; N, 16.92; Found: C, 45.51; H, 4.47; N, 16.60.

EXAMPLE 5 7-(a-Aminophenylacetamido)-3-(S-methyl-1,2,4-triazo1-3-y1thiomethyl)-3-cephem-4-carboxylic acid The title compoundwas obtained when 3-mercapto- 5-methy1-l,2,4-triazole was used in theprocedure of Example 1. Calculated for C, H N O.,S .1.25 H O: C, 47.24;H, 4.69; N, 17.29; Found: C, 47.39; H, 4.81; N, 16.80.

EXAMPLE 6 7-(a-Aminophenylacetamido)-3-(4-methyl-5- trifluoromethyl- 1,2,4-triazol-3-ylthiomethyl )-3- cephem-4-carboxylic acid When3-mercapto-4-methyl-5-trifluoromethy1-1 ,2,4- triazole was used in theprocedure of Example 1, the title compound was obtained; m.p. 162l65(dec.);

Calculated for C H, F N O S .l.5H O: C, 43.24; H, 3.99; N, 15.13; Found:C, 43.63; H, 3.61; N, 14.70.

EXAMPLE 7 EXAMPLE 8 When the appropriately substituted 3-mercapto-1,2,4-triazo1e was substituted for3,4-dimethyl-5-mercapto-1,2,4-triazole in the procedure of Example 1 thefollowing cephalosporins were obtained: 7-(a-aminophenylacetamido)-3-(l-ethyl-1,2,4-triazol- 3-ylthiomethyl)-3-cephem-4-carboxylic acidCalculated for C2 H22N O4S2-l.5 H20: C, H, 5.02; N, 16.76;

Found: C, 47.64; H, 4.63; N, 16.79 7-(a-aminophenylacetamido)-3-(l-isopropyl-1,2,4- triazol-3-y1thiomethy1)-3-cephem-4-carboxylic acidCalculated for C ,H N.;O.,S .0.5 H O: C, 50.69; H, 5.06; N, 16.89;

Found: C, 50.43; H, 5.31; N, 17.147-(a-aminophenylacetamido)-3-(4n-propyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid Calculated for C ,H.,N O S 01.5 H O: C, 48.92; H, 5.28; N, 16.30;

Found: C, 48.95; H, 4.98; N, 16.11

7-( a-aminophenylacetamido)-3-(4-isopropyll ,2,4-triazol-3-y1thiomethy1)-3-cephem-4-carboxy1ic acid Calculated for C ,H NO S .1.5 H O: C, 48.92; H, 5.28; N, 16.30;

Found: C, 49.35; H, 4.90; N, 15.927-(a-aminophenylacetamido)-3-(4-n-butyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid Calculated for CH,,,N O S .1.25 H O: C, 50.32; H, 5.47; N, 16.00;

Found: C, 50.48; H, 5.24; N, 15.657-(a-aminophenylacetamido)-3-(4-a11yl-1,2,4-triazo1-3-ylthiomethyl)-3-cephem-4-carboxylic acid Calculated for C ,H N O S.1.25 H O: C, 49.54; H, 4.85; N, 16.51;

Found: C, 49.82; H, 4.56; N, 16.03

7-( a-aminophenylacetamido)-3-( S-ethyll ,2,4-triazo1'3-ylthiomethy1)-3-cephem-4-carboxylic acid Calculated for C H N O S .2 HO: C, 47.05; H, 5.13; 16.46;

Found: C, 46.85; H, 4.72; N, 16.227-(a-aminopheny1acetamido)-3-(S-n-propyl-1 ,2,4-triazo1-3-y1thiomethyl)-3-cephem-4-carboxy1ic acid Calculated for C H NO S .l.25 H O: C, 49.35; H, 5.23; N, 16.44;

Found: C, 49.74; H, 5.40; N, 15.947-(oz-aminophenylacetamido)-3-(S-isopropyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid Calculated for C ,H NO S .H O: C, 49.79; H, 5.17; N, 16.59;

Found: C, 49.98; H, 5.03; N, 16.597-(a-aminophenylacetamido)-3-(5cyc1opropyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxy1ic acid Calculated for C H NO S .H O: C, H, N, 16.66;

Found: C, 50.32; H, 4.61; N, 16.34

6 7-(a-aminophenylacetamido)-3-(S-methoxymethyll ,2,4-triazol-3ylthiomethyl)-3-cephem-4-carboxylic acid Calculated for C20H22N05S2L520: C, H, 4.87; N, 16.24;

Found: C, 45.69; H, 4.70; N, 15.64 7-(a-aminophenylacetamido)-3-(l-ethyl-S-methyll ,2 ,4-triazol-3-y1thiomethyl )-3-cephem-4-carboxylicacid Calculatgd for C21Hg4N304S2-0.75 H20: C, H,

' Found: C, 50.23; H, 5.12; N, 16.74

7-(a-aminopheny1acetamido)-3-(4-ethyl-5-methyl- 1,2,4-triazo1-3-ylthiomethyl )-3-cephem-4-carboxylic acid Calculated forC H N O S .2 H O: C, 48.08; H, 5.38; N, 16.02

Found: C, 48.30; H, 4.98; N, 15.39 7-(a-aminophenylacetamido)-3-(1,3-dimethyll ,2,4- triazol-S-ylthiomethyl)-3-cephem-4-carboxylic acidCalculated for C H N O S .H O: C, 48.77; H, 4.91; N, 17.06;

Found: C, 49.06; H, 4.65; N, 16.89

EXAMPLE 9 7-(a-Aminophenylacetamido )-3-( 1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid When S-mercapto-l,2,3-triazo1ewas reacted according to the procedure of Example 1 the title compoundwas prepared as the trifluoroacetate salt. Calculated forCwHwNsO4S2-C2HF302I C, H, 3.42; N, 14.89; Found: C, 42.83; H, 3.63; N,15.13.

EXAMPLE l0 7-( a-Amino-p-hydroxyphenylacetamido)-3-( 1,2,3-tria2o1-4-y1thiomethyl)-3-cephem-4-carboxylic acid To a stirred solutionof N-butoxycarbonyl-p-hydroxyphenylglycine (10.75 g, 0.0375 mol) in dryTHF (150 ml) was added triethylamine (5.2 m1, 0.0375 mol). The mixturewas cooled to -10 and then isobutyl chloroformate. (4.92m1, 0.0375 mol)was added dropwise over a 10 minute period. The reaction mixture wasstirred at l0 for minutes and then a cold solution of 7-ACA (10.1 g,0.0375 mol) in 50 percent aqueous THF m1) and triethylamine (6.75,0.0487 mol) was added over a 15 minute period. The reaction was stirredat '5 to 0 for 1 hour and at room temperature for 2 hours. The organicsolvents were evaporated and water ml) was added to the aqueous residue.The solution was extracted with ethyl acetate and the aqueous phase wasseparated, covered with fresh ethyl acctate, acidified to pH 2.8, andfiltered. The phases were separated and the acidic solution reextractedwith ethyl acetate. The extracts of the acidified aqueous solution werecombined, dried, and evaporated to give7-(aamino-p-hydroxyphenylacetamido)cephalosporanic acid.

A mixture of the above product (3.0 g, 0.00493 mol) in pH 6.4 buffer (30ml) was treated with NaHCO (1.085 g, 0.01233 mol) and then4-mercapto-1,2,3- triazole (0.748 g, 0.0074 mol). The solution waswarmed to 70 and stirred at 70 i 3 for 2.75 hours. The solution wascooled, filtered, and acidified to pH 2.5 producing a residue. Thesolvents were decanted and the residue washed with water. The productwas dissolved in ethyl acetate, washed with water, dried,

and evaporated to the N-protected product which was reprecipitated fromacetone-chloroform.

The protected product was stirred at to with a 9:1 trifluoroaceticacidzanisole solution for 70 minutes. The solvents were evaporated andthe residue was poured with rapid stirring into ether (350 ml). Theproduct was collected, washed with ether and triturated with acetone.Calculated for c, H, N,0 s .21-i 0; C, 43.37; H, 4.45; N, 16.86; Found:C, 43.67; H, 4.14; N, 16.62.

EXAMPLE 1 1 Use of the t-butoxycarbonyl derivative of ap-chloroerr-aminophenylacetamido, p-nitro-aaminophenylacetamido,3,4-dimethoxy-ozaminophenylacetamido,3-trifluoromethylwzaminophenylacetamido, a,p-diaminophenylacetamido orp-methyl-a-aminophenylacetamidocephalosporanic acid and3,4-dimethyl5-mercapto-1,2,4-triazole in the procedure of Example givesthe corresponding 7-(aamino substitutedphenylacetamido)-3-(3,4-dimethyll,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.

EXAMPLE 12 EXAMPLE 13 When an equivalent amount of the t-butoxycarbonylderivative of 7-(3,4-dichloro-aaminophenylacetamido)cephalosporanicacid, 7-(phydroxymethyl-a-aminophenylacetamido)cephalosphoranic acid,7-(p-aminomethyl-aaminophenylacetamido)cephalosporanic acid, 7-(3,5-dihyrodxy-a-aminophenylacetamido)cephalosporanic acid,7-(3-chloro-4-hydroxy-aaminophenylacetamido)cephalosporanic acid, 7-(2-chlor0-4-hydroxy-a-aminophenylacetamido)cephalosporanic acid,7-(2-fluoro-4-hydroxy-aaminophenylacetamido)cephalosporanic acid, 7-(3-fluoro-4-hydroxy-waminophenylacetamido)cephalosporanic acid,7-(4-isopropyl-a- .aminophenylacetamido )cephalosporanic acid, 7-( 4-bromo-a-aminophenylacetamido)cephalosporanic acid,7-(3-fluoro-a-aminophenylacetamido)cephalosporanic acid, or 7-(2-chloro-aaminophenylacetamido)cephalosporanic acid and 3,4-'

dimethyl-S-mercaptol ,2,4-triazole .are substituted for the startingmaterials in the procedure of Example 10,

,the corresponding 7-substituted a-aminophenylacetamido-3-(3,4-dimethyll ,2,4-triazolyl-5-ylthiomethyl)- 3-cephem-4-carboxylicacidis obtained.

EXAMPLE 14 Use of the t-butoxycarbonyl derivatives of apchloro-a-aminophenylacetamido, p-hydroxy-aaminophenylacetamido,p-nitr0-aaminophenylacetamido,p-hydroxy-m-methoxy-aaminophenylacetamido,3,4-dimethoxy-aaminophenylacetamido,p-methoxy-m-hydroxy-aaminophenylacetamido,3-trifluoromethyl-aaminophenylacetamido,3,4-dihydroxy-aaminophenylacetamido, a,p-diaminophenylacetamido,p-hydroxymethyl-a-aminophenylacetamido,paminomethyl-a-aminophenylacetamido 3,S-dihydroxy-a-aminophenylacetamido,2-chloro-4-hydroxytil-aminophenylacetamido,3-chloro-4-hydroxy-aaminophenylacetamido,2-fluoro-4-hydroxy-aaminophenylacetamido,3-fluoro-4-hydroxy-aaminophenylacetamido, orp-methyl-aaminophenylacetamidocephalosporanic acid and 5-methyl-3-mercapto-l,2,4-triazole in the procedure of Example 10 givesthe corresponding 7-(a-amino substituted phenylacctamido)-3-( S-methyl-l,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid.

EXAMPLE 15 Use of l-methyl-S-mercapto-l,2,3-triazole, l-ethyl-5-mercapto-l ,2,3-triazole, 2-methyl-5-mercapto-l ,2,3- triazole,l-methyl-4-mercapto-l ,2,3-triazole, 2-methyl- 4-mercapto-l,2,3-triazole, 4,5-diethyl-3-mercapto- 1,2,4-triazole,4-ethyl-3-mercapto-5-methyl-l ,2,4- triazole, or5-ethyl-3-mercapto-4-methyl-1,2,4-triazole in the procedure of Example 1gives the corresponding 7-(a-aminophenylacetamido)-3-(heterocyclicthiomethyl)-3-cephem-4-carboxylic acid.

EXAMPLE 16 Use of 3-mercapto-l-n-propyl-l,2,4-triazole, 3-mercapto-Z-n-propyl-1,2,4-triazole, 3-mercapto-4,5- di-n-propyl-l,2,4-triazole, 3-mercapto-2-isopropyl- 1,2,4-triazole,3-mercapto-4,5-diisopropyl-1,2,4- triazole,1-allyl-3-mercapto-l,2,4-triazole, 2-allyl- S-mercapto-l ,2,4-triazole,5-allyl-3-mercapto-l ,2,4- triazole, 4,5-diallyl-3-mercapto-l,2,4-triazole, lcyclopropyl-3-mercapto- 1 ,2,4-triazole, 2-cyclopropyl-3-mercapto-1,2,4-triazole, 4-cyclopropyl-3-mercapto- 1,2,4-triazole, and4,5-dicyclopropyl-B-mercapto- 1,2,4-triazole in the procedure of Example1 gives the corresponding 7-(a-aminophenylacetamido)-3- (substituted- 1,2,4-triazol-3-thiomethyl )3cephem-4- carboxylic acid.

EXAMPLE 17 When the t-butoxycarbonyl derivative ofp-hydroxyphenylglycine is reacted with the appropriate 7-amino-3-heterocyclicthiomethyl-3-cephem-4-carboxylic acid according to theprocedure of Example 1 the following compounds are obtained:

7-(a-amino-p-hydroxyphenylacetamido)-3-(4- methyl- 1,2,4-triazol-3-ylthiomethyl )-3-cephem-4- carboxylic acid7-(a-amino-p-hydroxyphenylacetamido)-3-(4,5-

dimethyl-l ,2,4-triazol-3-ylthiomethyl )-3-cephem- 4-carboxylic acid7-(a-amino-p-hydroxyphenylacetamido )-3-( 1- methyl- 1,2,3-triazol-4-ylthiomethyl )-3-cephem-4- carboxylic acid 7-(a-amino-p-hydroxyphenylacetamido)-3-( 1- methyl-l,2,3-triazol-5-ylthiomethyl )-3-cephem-4- carboxylic acid7-(a-amino-p-hydroxyphenylacetamido)-3-( 2-methyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4- carboxylic acid EXAMPLE18 When 3,4-dihydroxyphenylglycine is substituted forp-hydroxyphenylglycine in Example 17, the corresponding7-(a-amino-3,4-dihydroxyphenylacetamido)-3-(heterocyclicthiomethyl)-3-cephem-4-carboxylic acid is obtained.

EXAMPLE 19 When 4-hydroxy-3-methoxyphenylglycine is substituted forp-hydroxyphenylglycine in Example 17, the corresponding7-(a-amino-4-hydroxy-3-methoxyphenylacetamido)-3-heterocyclicthiomethyl- 3-cephem-4-carboxylicacid is formed.

EXAMPLE 20 When 3-hydroxy-4-methoxyphenylglycine is substituted forp-hydroxyphenylglycine in Example 17, the corresponding7-(a-amino-3-hydroxy-4-methoxyphenylacetamido)-3-heterocyclicthiomethyl- 3-cephem-4-carboxylicacid is obtained.

EXAMPLE 21 The compounds enumerated in Example 17 are also prepared byreacting 7-(a-amino-phydroxyphenylacetamido)cephalosporanic acid withthe appropriate mercaptotriazole according to the procedure of Example10.

EXAMPLE 22 An injectable pharmaceutical composition is prepared bydissolving 500 m.g. of sodium7-(a-aminophydroxyphenylacetamido)-3-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylate in 2 ml. of sterile water on normalsaline solution.

Any of the above disclosed cephalosporins may be formulated in a similarmanner.

EXAMPLE 23 An antibacterial capsule has the following components:cephalosporin (500 mg.), lactose (250 mg.) and magnesium stearate (75mg.).

EXAMPLE 24 The desired product was eluted with 3 percent methawith ethylacetate. The combined extracts were dried no] in chloroform.

The sodium salt was prepared by dissolution of the free acid in coldmethanol and adjustment of the solution to pH 6.9 with a 5 percentmethanolic sodium methoxide solution. The salt was precipitated with theaddition of ether; mp 210 (dec). Calculated for C HmN O S NaH O: C,44.34; H, 3.72; N, 14.37; Found: C, 44.20; H, 4.18; N, 14.17.

' EXAMPLE 2s 7-Mandelamido-3-(4-methyl-3-trifluoromethyll ,2,4-triazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid To a cooled solutionof O-tetrahydropyranylmandelic acid (4.73 g, 0.02 mol) and N-hydroxysuccinimide (2.3 g, 0.02 mol) in anhydrous tetrahydrofuran wasadded dicyclohexylcarbodiimide (4.12 g, 0.02 mol). After stirring 7hours at ice bath temperature, the reaction was allowed to stand at roomtemperature overnight. The dicyclohexylurea was removed by filtrationand the filtrate was evaporated to yield the succinimide ester. I

7-Amino-3-(4-methyl-3-trifluoromethyl-l,2,4-triazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid was preparedaccording to the procedure of Example 1 by substituting5-mercapto4-methyl-3-trifluoromethyll ,2,4-triazole for3,4-dimethyl-5-mercapto-1,2,4-triazole.v

To a cooled solution of this 7-aminocephem compound (6.3 g, 0.016 mol)in dry pyridine ml) containing triethylamine (3.4 g) was added thesuccinimide ester (5.5 g, 0.016 mol). The reaction was stirred for 3hours at room temperature and then poured into water (600 ml) that hadbeen acidified to pH 2. The precipitated solid was collected, dissolvedin ethyl acetate, and separated from insoluble material. Concentrationgave the product which was purified further by trituration withether-petroleum ether.

The above product (4.9 g, 0.0078 mol) was stirred in 14 ml ice coldtrifluoroacetic acid for 45 minutes. the trifluoroacetic acid wasremoved in vacuo and the residue triturated. with ether to yield thesolid title compound; mp 135-318. Calculated for C20H gF3N5O5S ./2H O:C, H, N, Found: C, 46.27; H, 3.84; N, 12.56.

EXAMPLE 26 7-Mandelamido-3-( l-methylimidazol-2-ylthiomethyl3-cephem-4-carboxylic acid A solution of 7.62 g of7-mandelamidocephalosporanic acid methanolate, 2.94 g of NaHCO and 3.0 gof Z-mercaptol-methylimidazole in a mixture of 50 ml of water and 25 mlof acetone was maintained at reflux for minutes. The solution wasdiluted with 75 ml of water and adjusted to pH 3.0. The precipitateproduced was filtered and washed with water to-give 1.72 g of productafter drying; mp l6871 (dec).

EXAMPLE 27 7-Mandelamido-3-(4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-( 4'methyl-l,2,4-triazole-3-ylthiomethyl 3-cephem-4-carboxylic acid was preparedfrom 7-ACA and 3-mercapto-4-methyl-1,2,4-triazole according to the firstparagraph of Example 1.

The above product (6.0 g, 18.3 mmol) was dissolved in 3% NaHCO (138 ml)and acetone (138 ml). After cooling to 15, a solution ofa-dichloroacetylmandloyl chloride (10.3 g, 36.6 mmol) in dry acetone (70ml) was added over a 35 minute period. After 45 minutes the solution wasallowed to rise to and then the pH was adjusted to with NaOH. Afterminutes a brown solid was filtered from the aqueous solution anddisgarded. The aqueous layer was washed with ether and then wasacidified to pH 3.8. A solid was collected and washed with acetone togive a solution EXAMPLE 287-Mandelamido-3-(3,4-dimethyl-1,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid7-Amino-3-(3,4-dirnethyl-1,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was prepared in the firstparagraph of the procedure of Example 1. This product was acylated bythe succinimide ester method of Example 25. After stirring the acylationreaction mixture 2.5 hours, the mixture was filtered and poured into alarge volume of ether. The precipitated solid was separated, dissolvedin chloroform, and washed with water. After drying, the solution wasevaporated to give the THP protected product. The product (3.0 g, 5.36mmol) was dissolved in methylene chloride (35 ml), cooled in ice, andtreated 10 minutes with ethereal hydrochloric acid (15 ml) during whichtime the hydrochloride salt of the title compound was formed andcollected; mp 110 (dec). Calculated for Found: C, 46.85; H, 5.27; N,12.28.

EXAMPLE 29 7-Mandelamido-3-(2-methyl-1,2,4-tria zol-3-ylthiomethyl)-3-cephem-4-carboxylic acid The title compound as itssodium salt was prepared when the procedure of Example 27 was followedusing 3-mercapto-2-methyl-l,2,4-triazole. Calculated for C 9HN5O5S2Na.2H2O-0-l CqHgOzi C, H, N, 13.48; Found: C, 44.51; H, 3.99; N,13.08.

EXAMPLE 3O 7-Mandelamido-3-(4-ethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid When the procedure of Example27 was used with 4-ethyl-3-mercapto-l,2,4-triazole, the title compoundwas obtained as its sodium salt. Calculated for C2oHgoN505S2Na.l.5HgO:C, H, N, Found: C, 45.93; H, 4.16; N, 13.10.

EXAMPLE 31 When 7-ACA,the appropriate mercaptotriazole, anda-dichloracetylmandeloyl chloride were reacted according to theprocedure of Example 27 the following compounds were obtained:7-Mandelamido-3-( S-n-propyl- 1 ,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid;

Calculated for C ,H N O -,S Na.l.5H O: C, 46.83; H, 4.68; N, 13.00;

Found: C, 46.62; H, 4.36; N, 12.947-Mandelamido-3-(S-cyclopropyl-1,2,4-triazol-3- ylthiomethyl)3-cephem-4-carboxylic acid;

Calculated for C ,H N -,O S Na.1.5H O: C, 47.01; H, 4.32; N, 13.05;

Found: C, 47.26, H, 4.08; N, 13.00 7-Mandelamido-3-( S-methoxymethyl-l,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid;

Calculated for C H N O S Na15H O: C, 44.44; H, 4.29; N, 12.96;

Found: C, 44.51; H, 402; N, 12.75 7-Mandelamido-3-(4-n-propyl-1,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid; Calculated forC ,H N,,O -,S Na.2H- O: C, 46.06; 4.79; N, 12.99;

Found: C, 45.98; H, 4.26; N, 12.43 7-Mandelamido-3-( 4-i-propyl-l,2,4-triazol-3- ylthiomethyl )-3-cephem-4-carboxylic acid; Calculatedfor C21H22N505S2N3..1.5Hz0i C, H, 4.68; N, 13.00;

Found: C, 46.94; H, 4.31; N, 12.93 7-Mandelamido-3-(4-allyl-l,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid;

Calculated for C21H20N505S2Na-L75Hg0I C, H, 4.38; N, 12.94;

Found: C, 46.68; H, 4.02; N, 12.55 7-Mandelamido-3-( l-methyl- 1,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid;

Calculated For C H N O S Na17SH O: C, 44.31; H, 4.21; N, 13.60;

Found: C, 44.74; H, 4.01; N, 13.04 7-Mandelamido-3-( l-i-propyl-l,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid;

5 Calculated for C ,H N O S Na.l.25H O: C, 47.23; H,

Found: C, 47.53; H, 4.39; N, 12.577-Mandelamido-3-(2,5-dimethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid;

Calculated for C20H2oN505S2Na.1.5H20: C, H, 4.42; N, 13.35;

Found: C, 46.23; H, 4.11; N, 12.75 7-Mandelamido-3-( l-ethyl-S-methyl-l,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid;

Calculated for C ,H N O,,S Na.H O: C, 47.63; H, 4.57; N, 13.22;

Found: C, 47.50; H, 4.50; N, 12.907-Mandelamido-3-(5-ethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid;

Calculated for C 1-l N,,O -,S Na.1.25H O: C, 44.64; H, 4.59; N, 13.02;

Found: C, 44.37; H, 4.10; N, 12.48 7-Mandelamido-3-(1-ethy1-1,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid;

Calculated for C2oH2oN5o5S2Na.H2OI C, H, 4.30; N, 13.58;

Found: C, 46.95; H, 4.00; N, 13.71 7-Mandelamido-3-(4-ethyl-5-methyl-1,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylic acid;

Found: C, 46.74; H, 4.40; N, 12.46 7-Mandelamido-3-( 1,2,3-triazol-4-ylthiomethyl)-3- cephem-4carboxylic acid;

Calculated for C gH N505S2Na-2H20: C, H, 3.99; N, 13.85;

Found: C, 42.46; H, 3.46; N, 13.57

13 7-Mande1amido-3-( 1-methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxy1ic acid; Calculated for C, H N O SNa.2H O: C, 43.93; H, 4.27; N, 13.48; Found: C, 43.69; H, 3.81; N, 13.21

EXAMPLE 32 3-Mercapto-5-methyl-l,2,4-triazole was reacted according tothe procedure of Example 27, toyield 7- mandelamido-3-( S-methyl-l,2,4-triazo1-3- ylthiomethyl)-3-cephem-4-carboxy1ic acid. The sodiumsalt wasprepared using the sodium methoxide method of Example 23.Calculated for C, H N O S Na.2H O: C, 43.93; H, 4.27 N, 13.48; Found: C,43.55; H, 3.92; N, 13.02.

EXAMPLE 33 EXAMPLE 34 When an equivalent amount of the appropriateheterocyclic thiol is substituted for- 3-mercapto-4-methyl-1,2,4-triazole in the procedure of Example 27, the fol- 4O lowingcephalosporins are obtained.

3-( l ,5-Dimethylimidazol-2-ylthiomethyl)-7-mandelamido-3-cephem-4-carboxylic acid3-(lmidazol-2-ylthiomethyl)-7-mandelamido-3- cephem-4'carboxylic acid3-[4(5)-Methylimidazol-2-ylthiomethyl1-7-mandelamido-3-cephem-4-carboxylic acid3-(4,S-Dimethylimidazol-Z-ylthiomethyl)-7-mandelamido-3-cephem-4-carboxylic acid EXAMPLE 35 When an equivalentamount of l-methyl-lH-l,2,4- triazole-S-thiol, 1-phenyl-3-methyl-1H- l,2,4-triazole- 5-thi0l, 3-phenyl-5-mercapto-l ,2,4-triazole, or S-ethyl-3-mercapto-4-methyl-l,2,4-triazole is substituted for3mercapto-4-methyl-l ,2,4-triazole in the procedure of I Example 27, thecorresponding 3-triazolylthiomethyl- 7-mandelamido-3-cephem-4-carboxylicacid is obtained.

EXAMPLE 36 When an equivalent amount of 7-(3,4-dichloromandelamido)cephalosporanic acid, 7-(4-methylmandelamido)-cephalosporanic acid, 7-(3,4-dimethoxymandelamido)-cephalosporanic acid, 7-(4-isopropylmandelamido)cephalosporanic acid, 7-(4- bromomandelamido)cephalosporanic acid, 7-( 3- fluoromandelamido)cephalosporanic acid,7-(4- nitromandelamido)cephalosporanic acid, ,7-(2-chloromandelamido)cephalosporanic acid, 7-(4-aminomandelamido)cephalosporanic acid, or 7-(3-trifluoromethylmandelamido)cephalosporanic acid is substituted for the7-mandelamidocephalosporanic acid, and3-mercapto-5-methyl-1,2,4-triazole is substituted for3-mercapto-l,2,4-triazole in the procedure of Example 24, thecorresponding 7-substitutedmandelamido-3-(5-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid is obtained.

EXAMPLE 37 Use of 3-mercapto-l-n-propyl-1,2,4-triazole, 3-mercapto-2-n-propyl' l ,2,4-triazole, 3-mercapt0-4,5- di-n-propyll ,2,4-triazole, 3-mercapt0-2-isopr0pyl- 1 ,2,4'triazole,3-mercapto-5-isopropyl-l ,2,4-triazole, 3-mercapto-4,5-diisopropyl-l,2,4-triazole, 1-a1ly1-3- merc'apto-l ,2,4-triazole,2-allyl-3-mercapto-1,2,4-

triazole, 5-allyl-3-mercapto-1,2,4-triaz0le, 4,5-diallyl-'3-mercapto-l,2,4triazo1e, 1:cyclopropyl-3-mercapt0- 1 ,2,4-triazole,2-cyclopropyl-3-mercapto-1 ,2 ,4- triazole,4-cyclopropyl-3-mercapto-1,2,4-triazole, and4,5-dicyclopropyl-3-mercapto-1,2,4-triazole in the procedure of Example27 gives the corresponding 7- mandelamido-3-( substituted 1,2,4-triazol-3 thiomethyl)-3-cephem-4-carboxylic acid.

EXAMPLE 38 When 7-(a-amino-p-hydroxyphenylacetamido)- cephalosporanicacid was reacted with 1-methyl-S-mercapto-tetrazole according to theprocedure of Example 10, 7-(a-amino-phydroxyphenylacetamido)-3l-methyltetrazol-S- ylthiomethyl)-3-cephem-4-carboxylic acid wasobtained. Calculated for C, H N,O S .H O: C, 43.63; H, 4.07; N, 19.79;Found: C,'43.71; H, 4.26; N, 19.43.

EXAMPLE 39 When, the t-butoxycarbonyl derivative of7-(aamino-p-hydroxyphenylacetamido)cephalosporanic acid and5-mercapto-4-methyl-1,2,3-triazole are reacted according to theprocedure of Example 10,7-(aamino-p-hydroxyphenylacetamido)-3-(4-methyl-1,2 ,3-

triazol-S-ylthiomethyl)-3-cephem-4carboxylic acid is obtained.

EXAMPLE 40 7 -(p-hydroxymandelamido)cephalosporanic acid To a solutionof p-hydroxymandelic acid (3.0 g, 0.018 mol) in a mixture of dry THFml)' and dry triethylamine (3 ml, 0.021 mol) was added N-trimethylsilylacetamide. The reaction was refluxed for 2 hours under anitrogen atmosphere. The solution was then cooled to l0" and isobutylchloroformate (2.7 ml, 0.018 mol) was added over a 20 minute period.After stirring for 20 minutes a solution of 7-ACA (4.89 g, 0.018 mol) in50% aqueous THF (60 ml) containing triethylamine (3 ml) was added over a30 minute period at 5 to l0. The solution was stirred at 0 for 1 hourand at room temperature for 1 hour. The THF was evaporated in vacuo and3% NaHCO was added to the turbid aqueous layer until it became clear.After the addition of water (50 ml) the solution is extracted with threeportions of ether which was discarded. The

7 aqueous phase is cooled, layered with ethyl acetate,

and acidified to pH 1.5 with 6N HCl. Phases were separated and theaqueous layer reextracted with ethyl acetate. The combined extracts werewashed with water, dried, and evaporated to the title product which waspurified as its triethylamine salt.

EXAMPLE 41 Qcaccmr x I 1 Y N HZSR COOM in which:

X and X are each hydrogen, lower alkyl of l-4 caratoms, cycloalkyl of upto 6 carbon atoms, alkenyl of up to 6 carbon atoms, lower alkoxyalkyl of2 to 8 carbon atoms, trifluoromethyl, amino, alkylamino, dialkylamino,lower alkylthio of up to 4carbon atoms, phenyl, and halo; and

M is hydrogen or an alkali metal.

2. A compound as claimed in claim 1, in which R is triazolyl,unsubstituted or substituted with l or 2 lower alkyl groups ortrifluoromethyl.

3. A compound as claimed in claim 2, in which R is 1,2,3-triazolyl,unsubstituted or substituted with l or 2 lower alkyl groups.

4. A compound as claimed in claim 2, in which R is 1,2,4-triazolyl,unsubstituted or substituted with l or 2 lower alkyl groups.

5. A compound as claimed in claim 3, being the compound7-mandelamido-3-( 1,2,3-triazol-4- ylthiomethyl) 3-cephem-4-carboxylicacid.

6. A compound as claimed in claim 4, being the compound7-mandelamido-3-( 4-methyll ,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid.

7. A compound as claimed in claim 4, being the compound 7-mandelamido-3-( S-methyll ,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid.

8. A compound as claimed in claim 4, being the coompound7-mandelamido-3-( l,2,4-triazol-3- ylthiomethyl)-3-cephem-4-carboxylicacid.

9. A compound as claimed in claim 4, being the compound7-mandelamido-3-(3,4-dimethyl-1,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.

10. A compound as claimed in claim 3, being the compound7-mandelamido-3-(4-methyl-l,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.

11. A compound as claimed in claim 1, in which X and X are both otherthan hydrogen.

12. A compound as claimed in claim 4, being the compound7-mandelamido-3-( l-methyl-l ,2,4-triazol-3ylthiomethyl)-3-cephem-4-carboxylic acid.

"H050 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,855,213 Dated December 17, 1971;.

. Inventor-(s) George L. Dunn and John R. E. Hoover It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

[- Column 3, line 1, change larger to -----large---. 1

Column 3, lines 31-66, correct to read3-(3,4-Dimethyl-l,2,4-triazol-5-ylthiomethyl)-7-(a-aminophe'nylacetamido-3-cephem-4carboxylic acid To a solution ofNaHCO (4.2 g., 0.05 mol.) in Water (50 ml.) was addd 7-ACA (6.8 g.,0.025 mol.),

water (50 m1.) and acetone (25 ml.).- The resulting solution Column 3,line 39, change 55 NaHC0 to -,---57 NaHC0 Column 3, line 68, delete theWord "ether" where it last occurs Column 5, line 30, delete 'fO" after"S Column 7, line 50, change "dihyrodxy" to ---dihydroxy--.

Column 8, line 28, change "2-methy1" to ----4-methyl----. Column 10,line 43, change "135-31a" to ---135-13s---.

Column 12, line 11, change "402" to ---4.02---.

Column 13, line 20, change 'mercaptol" to ---mercapto-l--.

Column 13, line 32, change "cepham" to ------cephem-----;

0 Column 16, line 27, change "coompound" to ---compound---.

Signed and Scaled this Tenth Day of August 1976 Q [SEAL] Arrest:

' RUTH C. MASON C. MARSHALL DANN 4 Arresting Officer CommissionerofPalems and Trademarks

1. A COMPOUND OF THE FORMULA
 2. A compound as claimed in claim 1, inwhich R1 is triazolyl, unsubstituted or substituted with 1 or 2 loweralkyl groups or trifluoromethyl.
 3. A compound as claimed in claim 2, inwhich R1 is 1,2,3-triazolyl, unsubstituted or substituted with 1 or 2lower alkyl groups.
 4. A compound as claimed in claim 2, in which R1 is1,2,4-triazolyl, unsubstituted or substituted with 1 or 2 lower alkylgroups.
 5. A compound as claimed in claim 3, being the compound7-mandelamido-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid.
 6. A compound as claimed in claim 4, being the compound7-mandelamido-3-(4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid.
 7. A compound as claimed in claim 4, being thecompound7-mandelamido-3-(5-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid.
 8. A compound as claimed in claim 4, being thecoompound7-mandelamido-3-(1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid.
 9. A compound as claimed in claim 4, being the compound7-mandelamido-3-(3,4-dimethyl-1,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
 10. A compound as claimed in claim 3, being thecompound7-mandelamido-3-(4-methyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.
 11. A compound as claimed in claim 1, in which X andX1 are both other than hydrogen.
 12. A compound as claimed in claim 4,being the compound7-mandelamido-3-(1-methyl-1,2,4-triazol-3ylthiomethyl)-3-cephem-4-carboxylicacid.